Immunologic Contributions to the Endometriosis Phenotype

免疫学对子宫内膜异位症表型的影响

基本信息

  • 批准号:
    10604909
  • 负责人:
  • 金额:
    $ 3.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Endometriosis, the presence of endometrial tissue at an extra-uterine site, is a common yet enigmatic gynecologic disease that dampens the quality of life for approximately 10-15% of reproductive-aged women. Although endometriosis is regarded as a benign condition, many women with this disease experience chronic episodes of debilitating pain, dyspareunia, dysmenorrhea, and/or infertility. Numerous theories have attempted to explain disease pathogenesis including retrograde menstruation, a genetic predisposition, and altered differentiation of non-uterine cells. Unfortunately, theories to date have failed to explain all incidences of disease occurrence. Thus, I am exploring the possibility that endometriosis is an adult-onset disease that emerges due to an early life disruption of endocrine-immune cross-communication. I hypothesize that an in utero toxicant exposure trains bone marrow-derived immune progenitor cells (BMDCs) and subsequently promotes the development of endometriosis in adulthood. Immune cell training refers to the development of memory of a previous infection, but it is unknown whether immune cells similarly “remember” a past toxicant exposure. Nevertheless, our laboratory has shown that in utero TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) exposure in mice results in a loss of uterine progesterone (P4) sensitivity and hyperinflammation as seen in women with endometriosis. Herein, I will utilize our established mouse model of toxicant exposure to determine if in utero TCDD exposure induces immune cell training prompting the development of the endometriosis-like uterine phenotype in adult mice. In Specific Aim 1, I will examine the relationship between toxicant-mediated peritoneal inflammation and reproductive dysfunction by characterizing the intraperitoneal immune phenotype and uterine phenotype of TCDD-exposed mice compared to wild-type C57/BL6 (WT) mice. Furthermore, I will determine if TCDD-mediated alterations of immune cells directly contribute to uterine dysfunction by adoptively transferring BMDCs from TCDD-exposed mice to control recipient mice. In Specific Aim 2, I will elucidate the molecular mechanisms underlying the TCDD-generated phenotype by examining the epigenetic, metabolic, and functional status of TCDD-exposed immune cells in comparison to unexposed immune cells. Overall, determining the specific contribution of immune cells to reduced P4 sensitivity within the uterus and identifying targetable pathways will determine the potential utility of immune cells as a diagnostic and/or therapeutic target. This proposal builds upon preliminary data that I have obtained and will provide me with the training I seek in reproductive toxicology, reproductive immunology, immunotoxicology, and immunometabolism. Aside from gaining this knowledge and technical skills, I will also gain necessary experience in data analysis, generation of manuscripts, communication of my results to scientific and lay audiences, and the formulation of testable hypotheses. At the conclusion of this fellowship, I will be well-positioned to undertake postdoctoral training in a leading laboratory and pursue my goal to be an independent investigator.
项目摘要 子宫内膜异位症,即子宫内膜组织出现在子宫外部位,是一种常见但神秘的疾病, 约10-15%育龄妇女的生活质量受到影响的妇科疾病。 虽然子宫内膜异位症被认为是一种良性疾病,许多妇女患有这种疾病的经验慢性 使人衰弱的疼痛、性交困难、痛经和/或不孕症的发作。无数的理论试图 解释疾病的发病机制,包括逆行月经,遗传易感性,和改变 非子宫细胞的分化。不幸的是,迄今为止的理论未能解释所有的疾病发生率 发生。因此,我正在探索子宫内膜异位症是一种成人发病的疾病, 内分泌免疫交叉通讯的早期中断。我假设子宫内的毒物 暴露训练骨髓来源的免疫祖细胞(BMDC),随后促进免疫祖细胞的增殖。 成年期子宫内膜异位症的发展。免疫细胞训练是指一种记忆的发展。 以前的感染,但它是未知的免疫细胞是否同样“记住”过去的有毒物质暴露。 尽管如此,我们的实验室已经表明,在子宫内TCDD(2,3,7,8-四氯二苯并-p-二恶英)暴露, 小鼠导致子宫孕酮(P4)敏感性丧失和炎症过度,如患有 子宫内膜异位症在此,我将利用我们建立的小鼠毒物暴露模型,以确定是否在 子宫内TCDD暴露诱导免疫细胞训练,促进子宫内膜异位症样病变的发展 成年小鼠中的表型。在具体目标1中,我将研究毒物介导的腹膜炎与 通过表征腹膜内免疫表型和子宫内膜炎和生殖功能障碍 TCDD暴露小鼠与野生型C57/BL 6(WT)小鼠相比的表型。此外,我将确定, TCDD介导的免疫细胞的改变通过过继性免疫反应直接导致子宫功能障碍。 将来自TCDD暴露小鼠的BMDC转移到对照受体小鼠。在具体目标2中,我将阐明 通过检查表观遗传学、代谢和细胞遗传学, TCDD暴露的免疫细胞与未暴露的免疫细胞相比的功能状态。总的来说, 确定免疫细胞对子宫内P4敏感性降低的特异性贡献, 靶向途径将决定免疫细胞作为诊断和/或治疗的潜在效用 目标该提案建立在我获得的初步数据的基础上,并将为我提供培训, 生殖毒理学、生殖免疫学、免疫毒理学和免疫代谢学。一边 在获得这些知识和技术技能的同时,我也将获得必要的数据分析经验, 手稿的生成,我的结果,科学和外行观众的沟通,并制定 可检验的假设在这个奖学金的结束,我将很好地定位进行博士后 在一个领先的实验室接受培训,并追求我成为一名独立调查员的目标。

项目成果

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Victoria Renee Stephens其他文献

Victoria Renee Stephens的其他文献

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